Type 2 diabetes associated with obesity and chronic inflammation is a major public health problem, which causes morbidity and death due to vascular complications. Before people develop type 2 diabetes, they almost always have pre-diabetes blood glucose levels that are higher than normal, but not high enough to be diagnosed as diabetes. There are 79 million pre-diabetics in the US. Recent studies show that long-term damage to the heart and vascular system occurs during pre-diabetes. Mechanisms responsible for this pathology are not understood. While oxidative stress and inflammation are key factors, treatment with antioxidants/anti-inflammatory agents has little effect on disease progression. Previous studies have demonstrated that vascular endothelial dysfunction occurs in pre-diabetic patients prior to development of type 2 diabetes. Thus, there is great need to define the mechanisms and metabolic processes that cause vascular injury and develop new therapies for prevention or reversal. Our expert interdisciplinary team will examine key pathways and biomarkers leading to vascular complications of type 2 diabetes. Our working hypothesis is that increased arginase and indoleamine 2,3-dioxygenase (IDO) activity cause vascular endothelial dysfunction and inflammatory injury by a positive feedback cycle of inflammatory cytokine production and oxidative stress. We will examine potential molecular mechanisms that lead to arginase and IDO activation, oxidant, and cytokine production, chronic subclinical inflammation, vascular dysfunction and tissue damage. We will use rodent models and translational experimental approaches to assess function of vascular and bone marrow derived cells in human subjects who are insulin resistant and pre-type 2 diabetic, in mice with obesity/type 2 diabetes, and in cultured cells. Additionally, leukocytes, circulating bone marrow-derived cells and plasma levels of arginase and IDO (activity/expression, substrate and products) will be assessed in relation to production of oxidants and cytokines. Our objective is to generate evidence of novel biomarkers and targets for interrupting disease progression. PUBLIC HEALTH RELEVANCE: Understanding the molecular mechanisms responsible for development of vascular disease in type 2 diabetes is necessary for successful treatment and prevention.